Could a bone marrow transplant to an unmatched donor be possible?
Patients who endure the lengthy and painful process of hematopoietic (blood-forming) stem cell transplants, otherwise known as bone marrow transplants, often suffer a lengthy and in many cases unsuccessful transplant. To receive donors, blood patients must first undergo high-dose, whole body chemotherapy and/or radiation in order to deplete their own defective stem cells. This needs to be performed to rid the patient’s body of their individual infected stem cells and to make room for the donor’s cells to engraft. This process is incredibly discomforting resulting in:
- increased infection rates
- disturbed immune system
- organ damage
If the donor isn’t an exact match, the patient must be suppressed for a prolonged period of time to prevent rejection. Two new studies from WorldCare Consortium™ member’s Boston Children’s Hospital and Dana Farber Cancer Institute, if they pass clinical trials, could potentially enable stem-cell transplant for a broader range of disorders and have the potential to allow for the use of unmatched donors.Pre-treatment will allow patients to avoid side effects.
Pre-treatment will allow patients to avoid side effects
Agnieszka Czechowicz began research on this topic back at Stanford University where she discovered that pre-treatment with an antibody that blocks the CD117 receptor, found exclusively on blood-forming stem cells, killing those cells selectively. This result meant that mice were able to tolerate donor stem cells safely, without any chemotherapy or radiation. Continuing these efforts, Czechowicz went onto her fellowship and residency at Boston Children’s Cancer and Blood Disorder Center in the lab of Derrick Rossi, Ph.D., of Boston Children’s Hospital program in Cellular and Molecular Medicine. During her residency to boost the effects of CD117 antibody she and her colleagues attached a drug called Saporin, which inhibits ribosomes, the protein-building structures. This drug had already been used in cancer patients and the team theorized it would kill patients own blood-forming stem cells more effectively. Their theory proved to be successful, more so than they anticipated.
Transplanting from any donor
The first study performed on mice showed that a single dose of the antibody-drug conjugate eliminated more than 99 percent of blood-forming stem cells while leaving other kinds of blood cells unharmed. This allowed for high levels of transplant stem-cells to thrive in the host animal. This meant that the mice now had successfully replaced their blood and immune system, at this point the animal’s immune cell function was preserved and responded effectively to pathogens.
The second study took this one step further and used mismatched donors. In this case, the mice also received immunosuppression, for only a short period. The mice tolerated this well and had a 50 percent engraftment rate meaning they could endure skin grafts from the same mismatched donor. These tests support the idea that it is possible in the near future to enable both stem cell transplant and subsequent solid organ transplant from any donor.
Czechowicz continues her efforts at Stanford University where she is now an Assistant Professor in the Division of Stem Cell Transplantation and Regenerative Medicine. Her next step is to complete further studies to confirm the safety and efficiency of the combination of using a human CD117 antibody. Magenta Therapeutics (Cambridge MA) has licensed the technology and is working on testing the approach on humans, they presented the pre-clinical data on CD117 antibody-drug conjugates at the American Society of Hematology meeting in December 2018, using Amanitin as a ribosome inhibitor. The National Institute of Health, Boston Children’s Hospital Trust New York Stem Cell Foundation and The Harvard Stem Cell Institute all support the current studies.